The use of radiation delivery sources such as stents or source wires to treat vascular lesions is well known in the medical field. The enhanced sensitivity of active, proliferating cells to the lethal effects of ionizing radiation prevents neointimal proliferation, vessel contraction and hyperplasia associated with restenosis following balloon dilatation procedures.
Unfortunately, vascular brachytherapy has a common side effect associated particularly with radioactive stents known as the candy-wrapper effect or edge effect, whereby tissue proliferation occurs at the extremes of the irradiated region. Vessel injury due to balloon or stent expansion and the rapid transition from radiated to non-radiated treatment regions are factors that may contribute to or cause the edge effect. It is believed that the edge effect is more severe in the presence of increased vessel injury manifested in forms such as barotraumas, expansion strains and endothelial cell denudation.
Porcine animal studies in which half-radioactive stents (radioactive only over half of their longitudinal length) were implanted in coronary arteries showed two regions of cell proliferation. Tissue proliferation was greatest in the center of the stent where the radioactivity of the stent went from a nominal value to a non-radioactive value. This type of transition also existed at the end of the radioactive portion of the stent, which also exhibited cell proliferation.
Thus, it is believed that the principal cause of the edge effect may be the occurrence of a sudden drop from high to low or zero radiation dose. Radiation delivered to a vessel, either affected or unaffected with lesions, may be interpreted as causing injury, which forces the vessel to heal. Cell proliferation and restenosis are forms of healing. Greater injury may result in greater healing responses, including cell proliferation, but increasing radiation dosage above a certain threshold may prevent such vessel healing and cell proliferation.
For example, a radiation delivery source such as a stent delivers radiation at a treatment level high enough to prevent cell proliferation. At the ends of the stent however, a short transition from a high to a low or no radiation-treated area creates a proximity of high radiation-treated and low or zero radiation-treated cells. Because cells react to injury to surrounding tissue, healthy tissue near the radiation-treated tissue reacts with unwanted cell growth. The low or zero radiation-treated tissue experiences minimal injury, but responds to the injury of the adjacent high radiation-treated tissue. In essence, there is not enough of a radiation dose delivered near the stent ends to prevent cell proliferation to surrounding tissue. Cell proliferation and restenosis may be stimulated by radiation injury to the nearby high radiation tissue even though the radiation is used initially to inhibit cell proliferation and restenosis to the lesion area.
Anti-proliferative drugs used to treat vascular lesions may also result in unwanted side effects comparable to radiation therapy. In addition to restenosis forming at the extremes of the treated region, healing and regeneration of the endothelial layer lining the cell wall may be delayed. For example, drugs selected for delivery by stents are often very toxic and potent, killing endothelial cells in the process. Endothelial cells are essential to maintain vascular homeostasis of the vessel.
Thus, what is needed is a radiation delivery apparatus and method that minimize or prevent cell proliferation at the ends of a radiation delivery source or radioactive region. A radioactivity gradient at the ends of a delivery source or region would increase the dose transition length from high to low or zero radiation. Consequently, cell proliferation from nearby tissue would be minimized or prevented. Similarly, drug gradients on drug delivery sources would prevent cell proliferation or minimize toxic effect of drugs at the ends of the delivery source and allow for a gradual, controlled healing to occur and progress into the center of the device.